Sitamaquine as a putative antileishmanial drug candidate: from the mechanism of action to the risk of drug resistance

Loiseau, Philippe M.; Cojean, Sandrine; Schrével, Joseph

doi:10.1051/parasite/2011182115

Cited by 83 publications

(48 citation statements)

References 26 publications

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“…Interestingly however, (+)-anolobine (7) was the most active against L. donovani (IC 50 =14.59 µm) and has IC 50 value of about twice that of the standard drug, Pentamidine (IC 50 =7.7 µm). Its IC 50 value also falls within the range given for the putative antileishmania drug, sitamaquine (2.9 ≥ IC 50 ≤ 19.0 μm) [8]. 7 is therefore a potential candidate for further studies as an antileishmanial compound.…”

Section: Concentrationmentioning

confidence: 67%

“…As a result, the search for new drug prototypes is an important requirement that needs to be pursued until the burden of these diseases can be reduced or eliminated. In the past few years, the interest in natural products as a potential source for the treatment of parasitic diseases has increased [5][6][7][8]. Traditionally, plants have been used for the treatment of protozoan diseases and phytotherapy has over the years received considerable attention in the search for alternative compounds with antiparasitic activity [9,10].…”

Section: Introductionmentioning

confidence: 99%

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Antileishmanial and Trypanocidal Activities of Extracts and Aporphine Alkaloids Isolated from Monodora Genus (Annonaceae)

Dade¹,

Kablan²,

Attioua³

et al. 2017

J Pharmacogn Nat Prod

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Leishmaniasis and trypanosomiasis are protozoan diseases caused respectively by the kinetoplastid protozoan Leishmania parasites transmitted by the female phlebotomine sandflies and Trypanosoma parasites transmitted by the tsetse fly. In the search for agents from tropical medicinal plants to treat these two neglected tropical diseases, serially extracted petroleum ether, dichloromethane and methanol extracts of the leaves of Monodora crispata and Monodora brevipes, and eleven aporphines alkaloids isolated from the dried powdered leaves of the two plants were evaluated against Leishmania donovani promastigotes and Trypanosoma brucei brucei trypomastigotes. The extracts of both plants and the isolated compounds displayed varied levels of antiprotozoal activities. The oxoaporphine compounds, (+)-anolobine (7) and (+)-listeferine (8), exerted the most significant activity against L. donovani (IC 50 : 14.59 µM) and T. brucei brucei (LC 100 : 50.02 µM) respectively. This is the first report on the antiprotozoal activity of the isolated compounds. The results offer potential for further studies of the oxoaporphines for enhanced antiprotozoal activity.

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Section: Concentrationmentioning

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Antileishmanial and Trypanocidal Activities of Extracts and Aporphine Alkaloids Isolated from Monodora Genus (Annonaceae)

Dade¹,

Kablan²,

Attioua³

et al. 2017

J Pharmacogn Nat Prod

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“…Sin embargo, debe evaluarse con detenimiento los efectos adversos a nivel renal y el desarrollo de cuadros como la metahemoglobinemia (49).…”

Section: Discussionunclassified

Leishmaniasis visceral en América Latina y perspectivas terapéuticas

Yasnot

2017

Rev MVZ Córdoba

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In Latin America, visceral leishmaniasis is caused by Leishmania infantum. In this geographical area, main vectors associated with transmission are Lutzomyia longipalpis and Lutzomyia evansi, with dogs being incriminated as the main reservoir involved in transmission of the disease. This pathology primarily affects children between 0 -5 years, a highly susceptible population where socio-economic, environmental and nutritional factors affects the pathological outcome and increase the likelihood of vector-human contact. According to the World Health Organization (WHO) recommended treatment for Visceral Leishmaniasis is liposomal amphotericin B, a drug with a limited and variable availability between countries depending on market prices, which leaves pentavalent antimonial as the most widely used treatment despite the associated toxic effects. In the Americas, evidence on the efficacy of single-dose (monotherapy) and combination therapies as options for treating these parasites is required. Disease, drug therapy, Leishmania infantum, Lutzomyia, vector (Source: MeSH). Keywords: RESUMENLa Leishmaniasis visceral es una enfermedad causada en América Latina por Leishmania infantum, en esta área geográfica los principales vectores asociados a la transmisión son Lutzomyia longipalpis y Lutzomyia evansi, siendo el perro uno de los principales reservorios incriminados en su transmisión. Es una patología que afecta principalmente a la población infantil entre los 0 a 5 años, donde los factores socioeconómicos, ambientales y nutricionales son determinantes en el contacto con el insecto vector y el desenlace patológico. Según la Organización Mundial de la Salud el tratamiento recomendando para esta patología es la Anfotericina B liposomal, sin embargo, la disponibilidad del medicamento por el costo varía entre los diferentes países, dejando antimoniales pentavalentes como opción más utilizada, pese a los efectos tóxicos asociados. En el continente americano se requiere evidencia de la eficacia de monoterapias de una solo dosis y terapias combinadas, como opciones para el tratamiento de estas parasitosis. INTRODUCCIÓNLa Leishmaniasis visceral (LV) es una parasitosis causada por un protozoo flagelado del género Leishmania, en América Latina la especie responsable de esta forma clínica es Leishmania infantum, su ciclo de transmisión involucra un insecto vector perteneciente al género Lutzomyia, y animales reservorios, como el perro que se destaca por su papel en el ciclo de transmisión doméstica (1).El proceso infeccioso inicia cuando una hembra hematófaga del genero Lutzomyia se alimenta de sangre del hospedador liberando de sus glándulas salivares promastigotes metacíclicos, los cuales son fagocitados principalmente por macrófagos locales, al interior se transforman en amastigotes que se reproducen intracelularmente. Tras la ruptura del macrófago los amastigotes son liberados con la capacidad de infectar nuevas células, posteriormente migran al hígado, medula ósea y bazo (2) alterando la arquitectura esplénica y produc...

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“…The strong points of sitamaquine are its short elimination half-life that prevents the rapid emergence of resistance, and the oral route administration. The results of phase IIb clinical trials against VL in India and Kenya by GSK were encouraging [155], but the selection of a sitamaquineresistant L. donovani clone in the laboratory and some adverse effects, such as methemoglobinemia and nephrotoxicity evidenced in clinical trials, are being considered for a further development decision [156]. A second promising antileishmanial molecule in advanced stage of development is tafenoquine (Fig.…”

Section: Mid-and Long-term Therapeutic Optionsmentioning

confidence: 99%

New Chemotherapeutic Strategies Against Malaria, Leishmaniasis and Trypanosomiases

Zucca

Scutera²,

Savoia³

2013

CMC

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Due to the persistent lack of suitable vaccines, chemotherapy remains the only option for the treatment of patients infected by protozoan parasites. However, most available antiparasitic drugs have serious disadvantages, ranging from high cost and poor compliance to high toxicity and rapid induction of resistance. In recent decades basic research laboratories identified a considerable number of promising new molecules, but their development has not been pursued in depth by pharmaceutical firms because of poor prospects of economic return. The establishment of adequately funded public-private partnerships is currently reversing the trend. This review deals with new drugs against Plasmodium, Leishmania and Trypanosoma parasites, focusing on the molecules that are in the most advanced stage of development. The purpose of this article is to provide the reader with a panoramic view of the updated literature on the challenges and strategies of contemporary antiprotozoal drug research, paying the due attention to the already published reviews.Keywords: Antibiotics, antiprotozoal chemotherapy, Leishmania, natural products, Plasmodium, Trypanosoma. 4 INTRODUCTIONInfections caused by parasitic protozoa take an enormous toll on human health. Their prevalence is higher in tropical and equatorial countries, where the major number of deaths is due to malaria, leishmaniasis, and African and American trypanosomiasis. High mortality rates are associated to poor sanitary conditions, high percentages of untreated HIV-infected individuals, and lack of efficient prophylactic measures [1]. In the developed countries the situation is not so tragic, but nonetheless it has its drawbacks. If it is true that in these countries most HIV-infected patients are treated, the number of chronically immuno-deficient carriers of transplanted organs is set to grow. In these patients latent parasitic infections, such as leishmaniasis and toxoplasmosis, can reappear as opportunistic infections. Moreover, the climate changes linked to global warming in temperate countries are extending the insect vector habitats, as is the case of the northward spread of leishmania-transmitting sandflies, assessed by epidemiological surveys of canine leishmaniasis in Italy [2][3][4]. Some additional cases of parasitic infections have also been registered due to "transplant tourism", i.e. travel with the intent of receiving or donating an organ, a practice that is rapidly increasing [5]. A further danger for industrialized countries comes from massive migration of infected subjects from endemic countries: a typical example is the presence of thousands of Trypanosoma cruzi-infected people in North America and Spain [6].In the absence of prophylactic or curative vaccines the only available choice is chemotherapy. However, this relies on drugs which are tens of years old, afflicted with serious disadvantages, such as heavy side-effects, selection of resistant strains, or high production costs. Unfortunately, this situation is not likely to improve in the short t...

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Sitamaquine as a putative antileishmanial drug candidate: from the mechanism of action to the risk of drug resistance

Cited by 83 publications

References 26 publications

Antileishmanial and Trypanocidal Activities of Extracts and Aporphine Alkaloids Isolated from Monodora Genus (Annonaceae)

Antileishmanial and Trypanocidal Activities of Extracts and Aporphine Alkaloids Isolated from Monodora Genus (Annonaceae)

Leishmaniasis visceral en América Latina y perspectivas terapéuticas

New Chemotherapeutic Strategies Against Malaria, Leishmaniasis and Trypanosomiases

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